Leukocyte cell-surface proteins are of crucial immunological importance in providing the cell with a means of sensing, responding and interacting with the environment. One class of such proteins is the superfamily of 4-transmembrane proteins (TM4SF) which consists of at least 15 members (e.g. CD9, CD37, CD53, CD63, CD81, CD82, A15) that are variously expressed on leukocytes. The existence of so many different TM4SF molecules, as well as their expression in organisms as diverse as humans and schistosomes, suggest a key role in biology. More recently, the cDNA for a prostate cancer metastasis protein has been cloned and is found to be related to the same family of protein. No clear function about this family of protein has emerged but accumulating evidence indicates that these proteins are likely to have important functions in regulation of cell proliferation and activation.
There is another family of 4-transmembrane proteins which are structurally distinct from TM4SF. Until recently, the only two known members of this family were the .beta.-subunit of the high affinity IgE Fc receptor, Fc.sub..epsilon. RI.beta., and the B-cell specific antigen CD20.
Fc.sub..epsilon. RI is part of a tetrameric receptor complex consisting of an .alpha. chain, a .beta. chain and two .gamma. chains (Kinet et al., Proc. Natl. Acad. Sci. USA, 15:6483-6487 (1988)). Together, they mediate interaction with IgE-bound antigens leading to dramatic cellular responses, such as the massive degranulation of mast cells. Thought until recently to be expressed only in mast cells and basophils, the high-affinity receptor Fc.sub..epsilon. RI has been shown to be present also in Langerhans cells (Kinet, J. -P. et al., Proc. Natl. Acad. Sci. USA 85:6483-6487 (1988)), eosinophils (Sutton, B. J. and Gould, H. J., Nature (London) 366:421-428 (1993)) and peripheral monocytes. The .beta. subunit, Fc.sub..epsilon. RI.beta., is a 4-transmembrane protein with both the amino and carboxyl termini residing in the cytoplasm.
Atopy is generally defined as a disorder of Immunoglobulin E (IgE) responses to common antigens, such as pollen or house dust mites. It is frequently detected by either elevated total serum IgE levels, antigen specific IgE response or positive skin tests to common allergens. In principle, atopy can result from dysregulation of any part of the pathway which begins with antigen exposure and IgE response to the interaction of IgE with its receptor on mast cells, the high affinity Fc receptor Fc.sub..epsilon. RI, and the subsequent cellular activation mediated by that ligand-receptor engagement (Ravetch, Nature Genetics, 7:117-118 (1994)). Cookson et al., Lancet, 333:1292-1295 (1989) have reported a genetic link between generalized atopic IgE responses and a locus on human chromosome 11q.
Thus, FcRI plays a role in atopic diseases as well. Atopic diseases, which include allergy, asthma, atopic dermatitis (or eczema) and allergic rhinitis, together constitute one of the largest group of clinical disorders requiring medical intervention. In the United Kingdom alone, atopy gives rise to 3-5 million cases and as many as 2,000 deaths each year.
The human CD20 antigen (Tedder, T. F., et al., Proc. Natl. Acad. Sci. USA 85:208-212 (1988)), as well as its murine equivalent Ly-44 (Tedder, T. F. et al., J. Immunol. 141:4388-4394 (1988)), are expressed only in B-cells. Functional studies with different CD20 antibodies indicate that CD20 is involved in the regulation of B-cell activation (Clark, E. A. and Lane, J. L. Annu. Rev. Immunol. 9:97-127 (1991)). The CD20 protein also contains four transmembrane domains with the amino and carboxyl ends on the cytoplasmic side of the cell membrane. CD20 is believed to play a direct role in transmembrane Ca.sup.-' flux. It is not clear, however, whether CD20 alone is a channel protein, it functions as such in association with other proteins or it induces the activation of resident membrane channels.